心血管リスク評価と脂質管理の進展

1960年から2026年までのライフコース分析

はじめに

循環器医学の歴史的軌跡は、終末期臨床イベントの受動的な管理から、生体生理学的駆動因に焦点を当てた、先制的かつライフコース全体を見据えたパラダイムへの深遠な移行を表している。 動脈硬化. 20世紀半ば以降、脂質代謝に対する医学界の理解は、大まかなものへの着目から進化してきた。 総コレステロール 測定値から～の微妙な理解へ リポタンパク質 粒子状物質の濃度、遺伝的素因、および動脈硬化性曝露の累積負荷。2026年現在、臨床的焦点は、先進的な手法を活用して、症候性疾患の発症の何十年も前にリスクを特定することへと移行している。 バイオマーカー 〜など アポリポ蛋白 Bアポリポ蛋白B) および リポタンパク(a) [Lp(a)]、および組み込むことで ポリジェニックリスクスコア 標準化された評価ツールに.¹

コレステロールガイドラインと臨床目標の歴史的変遷

の概念化 コレステロール 血管病変の主要な原因としての特定は、即座に合意が得られたものではなく、数十年間にわたる疫学的な観察を通じて苦労の末に勝ち取られた進展であった。 治験 証拠。1960年代、「コレステロール論争」は最高潮に達しており、研究者たちは血中脂質が単なる老化の相関因子なのか、それとも心疾患の原因物質なのかを議論していた。.²

NCEP以前の時代と脂質仮説の台頭

Prior to the formalization of national guidelines, ‘acceptable’ total cholesterol levels were remarkably high by modern standards. In the 1960s and early 1970s, clinicians commonly regarded total cholesterol levels of 240 mg/dL or higher as normal for aging adults. This perception was rooted in average population levels of the time, where the mean total cholesterol for U.S. adults aged 20–74 was approximately 222 mg/dL between 1959 and 1962.³ Early interventions were primarily dietary. The American Heart Association issued its first formal dietary recommendations in 1961 and updated them in 1968, advocating restriction of 飽和脂肪酸 そして dietary cholesterol. These early targets reflected a nascent understanding that dietary saturated fat influenced serum cholesterol levels, though the magnitude of this effect was often overestimated in isolation from the broader dietary context.⁴

The National Cholesterol Education Program and the Adult Treatment Panels

The 1980s marked a pivotal transition with the establishment of the National Cholesterol Education Program (NCEP). The release of the first Adult Treatment Panel (ATP I) report in 1988 provided the first standardized framework for identifying and treating high blood cholesterol.⁵

Table 1. Evolution of U.S. Cholesterol Guidelines, 1988–2026

Guideline Report	Year	Primary Focus	LDL-C Targets / Key Changes
NCEP ATP I	1988	一次予防; total cholesterol and LDL-C screening.	LDL-C <160 mg/dL (low risk); <130 mg/dL (high risk).
NCEP ATP II	1993	二次予防 for established CHD; emphasized HDL-C.	LDL-C <100 mg/dL for secondary prevention.
NCEP ATP III	2001	10-year risk assessment (Framingham); CHD ‘risk equivalents’ including 糖尿病.	Optimal LDL-C <100 mg/dL; low HDL-C defined as <40 mg/dL.
ATP III Update	2004	Intensified therapy for ‘very high risk’ individuals.	Optional LDL-C <70 mg/dL for very high risk.
2013 ACC/AHA	2013	Abandoned treat-to-target; identified four スタチン benefit groups.	High- vs. moderate-intensity statin therapy; no specific LDL-C target.
2018 AHA/ACC Multisociety	2018	Return to thresholds; risk-based escalation with non-statin agents.	LDL-C <70 mg/dL (high risk); <55 mg/dL (very high risk).
2026年 ACC/AHA Dyslipidemia ガイドライン	2026	Life-course prevention; 数式を防ぐ for 10- and 30-year risk; ApoB and Lp(a) screening.	LDL-C <55 mg/dL (very high risk); universal one-time Lp(a) testing.

NCEP = National Cholesterol Education Program; ATP = Adult Treatment Panel; ACC = American College of Cardiology; AHA = American Heart Association.

The rationale for progressively lower targets was driven by a robust accumulation of evidence from ランダム化比較試験. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) in 1984 demonstrated that for every 1% reduction in total cholesterol, CHD risk fell by approximately 2%, providing an early statistical foundation for aggressive lipid-lowering.⁶ Subsequent trials in the 1990s and early 2000s—the Scandinavian Simvastatin Survival Study (4S), the Cholesterol and Recurrent Events trial (CARE), and the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study—consistently showed that lowering LDL-C reduced 主要心血管イベント (MACE), leading to broad adoption of the ‘lower is better’ philosophy.⁷

The 2013 Paradigm Shift and the Move to Statin Intensity

A significant disruption occurred in 2013 with the release of the ACC/AHA cholesterol guidelines. This report moved away from specific LDL-C numerical targets, instead identifying four ‘statin benefit groups’ where evidence for risk reduction was most compelling: (1) individuals with clinical atherosclerotic 心血管疾患 (ASCVD); (2) individuals with primary LDL-C elevations ≥190 mg/dL; (3) individuals aged 40–75 years with diabetes and LDL-C 70–189 mg/dL; and (4) individuals aged 40–75 years without clinical ASCVD or diabetes, with LDL-C 70–189 mg/dL and an estimated 10-year ASCVD risk ≥7.5%.⁸ This approach prioritized the intensity of statin therapy over the achievement of a specific LDL-C level. However, this shift was controversial, as many clinicians felt it reduced motivation for patient 固守 and neglected individual variability in drug response.⁹

The Return to Targets and the 2026 Life-Course Paradigm

The 2018 ACC/AHA Multisociety guidelines and the 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia restored explicit LDL-C treatment targets with a significantly expanded scope. Published in the Journal of the American College of Cardiology and co-published in 循環, the 2026 guideline emphasizes earlier risk assessment beginning at age 30 and mandates use of the PREVENT (Predicting Risk of Cardiovascular Disease EVENTs) equations to estimate both 10-year and 30-year lifetime risk.¹ For adults aged 30–79 years without known ASCVD and with LDL-C 70–189 mg/dL, the PREVENT-ASCVD equations classify 10-year risk as low (<3%), borderline (3% to <5%), intermediate (5% to <10%), or high (≥10%). For very high-risk individuals (defined as those with multiple major ASCVD events or one major event plus multiple high-risk conditions), the guideline recommends an LDL-C target of <55 mg/dL.¹ This reflects the modern understanding that atherosclerosis is a lifelong cumulative process, where the ‘area under the curve’ of atherogenic lipoprotein exposure determines ultimate event risk.¹⁰

Population Averages Versus Optimal Biological Health

A central theme in contemporary lipidology is the recognition that ‘average’ or ‘normal’ cholesterol levels in industrialized populations do not represent health but rather a high-risk baseline shaped by diet, physical inactivity, and metabolic disease.¹¹

NHANES Trends in Mean Cholesterol: 1960 to Present

Data from the National Health and Nutrition Examination Survey (NHANES) document a steady decline in mean total cholesterol among U.S. adults aged 20–74 years, from approximately 222 mg/dL in 1959–1962 to 197 mg/dL by 2007–2008.³ Despite this encouraging trend, the mean U.S. adult cholesterol profile continues to facilitate atherosclerotic 歯垢 progression. The prevalence of high total cholesterol (≥240 mg/dL) declined from approximately 20% in 1988–1994 to 11.3% in 2021–2023, though this plateau has persisted since approximately 2013–2014.¹²

Table 2. NHANES Trends in Total Cholesterol and LDL-C in U.S. Adults Aged 20–74 Years

NHANES Period	Mean Total Cholesterol (mg/dL)	Mean LDL-C (mg/dL)	Prevalence of High TC (≥240 mg/dL)
1959–1962	~222	N/A	High (estimated)
1971–1975	~216	N/A	N/A
1976–1980	~213	~137	N/A
1988–1994	~206	~129	~20%
2007–2008	~197	~116	~17%
2021–2023	N/A	N/A	~11.3%

Sources: Carroll et al. (2012); Curtin et al. (2024). N/A = data not available from cited surveys.

The prevalence of metabolic dysfunction—characterized by 肥満, hyperinsulinemia, and インスリン抵抗性—has shifted the ‘normal’ distribution toward higher 中性脂肪 and lower HDL-C, creating a population where the average individual is actively developing vascular 病変.¹³ In striking contrast, human neonates typically possess LDL-C levels between 30 and 70 mg/dL, consistent with levels observed in wild-type primates and other mammals that do not spontaneously develop atherosclerosis.¹⁴

Lessons from the Tsimane of the Bolivian Amazon

その チマネ population of the Bolivian Amazon provides a unique biological benchmark. A landmark 2017 cross-sectional コホート研究 掲載 ランセット found that the Tsimane have the lowest reported prevalence of coronary atherosclerosis of any population yet studied—five times lower than comparable U.S. populations.¹⁵ In a sample of 705 adults aged 40–94 years, 85% had a 冠動脈石灰化（CAC） score of zero, and among those aged over 75 years, 65% still had no measurable coronary 石灰化—a five-fold lower prevalence than age-matched Americans in the Multi-Ethnic Study of Atherosclerosis (MESA).¹⁵

The mean LDL-C of Tsimane participants was 91 mg/dL and mean HDL-C was 39.5 mg/dL.¹⁵ Notably, this low burden of atherosclerosis persisted despite elevated systemic 炎症: high-sensitivity C反応性タンパク質 exceeded the clinical cutoff of 3.0 mg/dL in 51% of Tsimane participants, attributable to a high infectious and parasitic burden rather than vascular inflammation.¹⁵ These findings suggest that atherosclerosis is not an inevitable consequence of aging or inflammation alone, but requires a critical threshold of circulating atherogenic lipoprotein exposure—a threshold exceeded in virtually all contemporary Western populations.¹⁵

Apolipoprotein B as a Superior Measure of Atherogenic Risk

While LDL-C measures the total mass of cholesterol within LDL particles, it does not account for the total number of atherogenic lipoprotein particles or the heterogeneity of their composition. Apolipoprotein B (ApoB) is the structural タンパク質 present in a 1:1 ratio on every potentially 動脈硬化惹起性粒子, including VLDL, IDL, LDL, and Lp(a).¹⁶

The Mechanistic Case for ApoB Superiority

The emerging consensus in lipidology holds that the total number of atherogenic particles is the primary driver of the ‘response-to-retention’ mechanism of atherosclerosis initiation. Atherosclerosis begins when アポB含有リポ蛋白 traverse the endothelial barrier and become trapped within the 内皮下プロテオグリカンマトリックス.¹⁷ Because each such particle carries one ApoB molecule, ApoB measurement directly quantifies the total atherogenic 粒子負荷 delivered to the arterial wall—a metric more physiologically precise than the cholesterol content of LDL particles alone.¹⁶

Discordance Between ApoB and LDL-C in Metabolic Disease

The limitations of LDL-C are most apparent in individuals with インスリン resistance, type 2 diabetes, or hypertriglyceridemia. Metabolic dysfunction leads to hepatic overproduction of large, triglyceride-rich VLDL particles. In the circulation, cholesteryl ester transfer protein (CETP) exchanges triglycerides from VLDL for cholesterol esters in LDL particles, and the resulting triglyceride-enriched LDL undergoes hydrolysis by hepatic lipase to yield small, dense LDL (sdLDL).¹⁸ These sdLDL particles are cholesterol-depleted per particle, producing paradoxically low LDL-C values despite a high total ApoB (and particle) count. A システマティックレビュー そして メタ分析 demonstrated that such ApoB/LDL-C 不一致 is prevalent in metabolic disease and is associated with significant underestimation of cardiovascular risk.¹³

Table 3. ApoB/LDL-C Discordance Patterns by Metabolic State

Metabolic State	LDL-C Level	ApoB Level	Clinical Implication
Healthy インスリン感受性	Concordant (e.g., 100 mg/dL)	Concordant (e.g., 80 mg/dL)	Risk accurately estimated by either metric.
Insulin resistance / type 2 diabetes	Discordantly low (e.g., 90 mg/dL)	Discordantly high (e.g., 110 mg/dL)	Risk underestimated by LDL-C alone.
High saturated fat intake (large LDL phenotype)	Discordantly high (e.g., 160 mg/dL)	Relatively lower (e.g., 100 mg/dL)	Risk may be overestimated by LDL-C.

Adapted from: Tsoupras et al. (2024); Fahed et al. (2022).

Analyses of NHANES data have shown that approximately 20% of the general U.S. population exhibits clinically significant discordance between ApoB and LDL-C, with this proportion rising substantially among those with メタボリックシンドローム.¹⁹ Individuals with high ApoB but concordantly low LDL-C demonstrate significantly higher rates of coronary 動脈 calcification and 慢性腎臓病 than those with the inverse pattern, confirming that particle number is the mechanistically relevant driver of アテローム発生.²⁰

Small, Dense LDL: The Mechanistic Link

Small, dense LDL particles are uniquely hazardous for three principal reasons. First, their reduced size facilitates penetration of the arterial 内膜. Second, they exhibit enhanced affinity for subendothelial proteoglycans, leading to prolonged retention at the site of atherogenesis. Third, they are more susceptible to oxidative modification—the prerequisite step for macrophage uptake and foam cell formation.²¹ Clinically, a patient with a ‘normal’ LDL-C but elevated ApoB or LDL particle number carries a risk profile that is systematically concealed by standard lipid screening.¹³

Lipoprotein(a): The Genetic Vanguard of ASCVD Risk

Lipoprotein(a) [Lp(a)] has only recently attained widespread clinical recognition despite being identified in the 1960s. Its Lp(a) levels are approximately 70–90% genetically determined by variation at the LPA gene locus and are not meaningfully altered by lifestyle modification or conventional statin therapy.²²

Role in Atherogenesis, Thrombosis, and Valvular Disease

Lp(a) consists of an LDL-like lipoprotein with an additional glycoprotein, apolipoprotein(a) [apo(a)], covalently attached to the アポB-100 molecule via a disulfide bond.²² This structural configuration confers dual pathogenicity: Lp(a) is both highly atherogenic through its retention in the 内皮下腔 and is potentially prothrombotic through the structural homology of apo(a) with プラスミノーゲン, which may interfere with fibrinolysis.²³ Elevated Lp(a) is also a major independent 危険因子 for calcific 大動脈弁 狭窄; individuals with the highest Lp(a) levels face substantially higher risk of aortic valve replacement or aortic valve-related death.²⁴

Screening Recommendations and Emerging Therapies

The 2026 ACC/AHA Dyslipidemia Guideline recommends at least one lifetime measurement of Lp(a) for all adults to identify individuals with high inherited cardiovascular risk.¹ Elevated Lp(a)—generally defined as ≥50 mg/dL (or ≥125 nmol/L)—affects an estimated 20–25% of the global population, representing over 1.5 billion individuals, and contributes substantially to residual cardiovascular risk that is not addressed by statin therapy.²³

Table 4. Emerging RNA-Based Therapies Targeting Lp(a) as of 2026

Treatment Class	Mechanism of Action	Lp(a) Reduction	Development Status (2026)
Antisense oligonucleotides (ASO)	Binds to LPA mRNA to promote degradation via RNase H.	~70–80%	ペラカルセン: Phase 3 cardiovascular outcomes trial (HORIZON) completed; results awaited.
siRNA therapies	Cleaves LPA mRNA via the RISC complex.	~80–95%	オルパシラン (OCEAN[a]-OUTCOMES trial ongoing); Lepodisiran (Phase 3).
Oral small-molecule inhibitors	Disrupts the hepatic assembly of apo(a) and ApoB.	Significant reduction	Muvalaplin: Phase 2 completed; Phase 3 planned.

Sources: Tsimikas (2022); Kronenberg & Mora (2025). RISC = RNA-induced silencing complex; mRNA = messenger RNA.

While these therapies are still awaiting definitive cardiovascular outcome trial results, they represent a transformative paradigm shift in our ability to pharmacologically address a previously ‘unreachable’ genetic risk factor.²⁵

Cardiovascular Mortality Trends: 1970 to 2022

The decline in cardiovascular mortality since 1970 represents one of the most remarkable public health achievements of the modern era. A comprehensive analysis of U.S. National Vital Statistics System data for adults aged 25 years and older, published in the 米国心臓協会誌 in 2025, found that in 1970 heart disease accounted for 41% of all deaths; by 2022, this had fallen to 24%—an overall reduction in age-adjusted heart disease mortality of 66%.²⁶

Deconstructing the Decline

Age-adjusted mortality from acute 心筋梗塞 (AMI) declined by 89% from 1970 to 2022, while total 虚血性心疾患 mortality fell by 81% over the same period.²⁶ A landmark analysis by Ford et al. (2007) decomposed the decline in U.S. 冠動脈疾患 deaths between 1980 and 2000, attributing approximately 44% to risk factor reductions (predominantly 喫煙 cessation, lower mean 血圧, and lower mean total cholesterol) and approximately 47% to improved medical and surgical treatments (including secondary prevention after MI, acute AMI treatments, and 心不全 management).²⁷

Table 5. Estimated Contributions to the Decline in U.S. Coronary Heart Disease Mortality, 1980–2000

因数分解する	Estimated Contribution	Primary Mechanisms
Risk factor reductions	~44%	Decline in smoking prevalence (~42% in 1965 to ~25% in 1995); lower mean 収縮期血圧; lower mean total cholesterol.
Medical and surgical treatments	~47%	Secondary prevention after MI (~11%); acute AMI treatments (thrombolytics, PCI) (~10%); heart failure management (~9%); coronary 血行再建術 (~5%).
Other / unexplained	~9%	Including changes in physical activity, diet, and unmeasured confounders.

Adapted from: Ford et al. N Engl J Med. 2007;356:2388–2398. MI = myocardial infarction; PCI = percutaneous coronary intervention.

However, a critical finding from the 2025 JAHA analysis reveals a concerning compositional shift: while deaths from acute myocardial infarction fell by 89%, mortality from non-ischemic heart conditions substantially increased. Deaths from heart failure rose by 146%, hypertensive heart disease by 106%, and arrhythmias by 450% over the study period.²⁶ This pattern indicates that modern medicine has succeeded in preventing death from acute ischemic events—largely by converting them into survivable occurrences—but that the underlying atherosclerotic disease process, and the chronic organ damage that accrues over decades, continues largely unabated.²⁶

Effectiveness of Statins: Relative Versus Absolute Risk Reduction

The success of statins is frequently expressed in terms of 相対リスク reduction (RRR). A Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis of data from 170,000 participants in 26 randomized trials demonstrated a consistent ~21% proportional reduction in major vascular events per 1.0 mmol/L (38.7 mg/dL) reduction in LDL-C.²⁸

Absolute Risk Reductions and the NNT Debate

Despite consistent relative benefits, a 2022 systematic review and meta-analysis of 21 eligible randomized trials published in JAMA Internal Medicine by Byrne et al. demonstrated that 絶対リスク reductions (ARRs) are substantially more modest, particularly in primary prevention settings.²⁹

Table 6. Relative Risk Reduction, Absolute Risk Reduction, and NNT for Statin Therapy (pooled primary and secondary prevention trials; mean follow-up 4.4 years)

Outcome	Relative Risk Reduction (95% CI)	Absolute Risk Reduction (95% CI)	Number Needed to Treat
All-cause mortality	9% (5–14%)	0.8% (0.4–1.2%)	~125
Myocardial infarction	29% (22–34%)	1.3% (0.9–1.7%)	~77
脳卒中	14% (5–22%)	0.4% (0.2–0.6%)	~250

Source: Byrne P, et al. JAMA Intern Med. 2022;182:474–481. CI = 信頼区間; NNT = number needed to treat (calculated from ARR).

This RRR/ARR discrepancy has fueled debate over the sufficiency of current lipid-lowering strategies, particularly in low-risk primary prevention populations where baseline event rates are low. However, the 2026 guideline framework advocates a ‘life-course’ perspective: while the 5-year ARR for a low-risk individual starting statin therapy in middle age may be modest, the cumulative prevention of atherosclerotic プラーク負荷 over 30–40 years could yield substantially larger lifetime benefits.¹ その CTT Collaboration has reinforced this point, demonstrating that the proportional risk reduction is consistent across all baseline risk levels, meaning individuals who initiate therapy earlier—when absolute risk is lower—may accumulate the greatest lifetime benefit.²⁸

Critical Synthesis: Toward a Precision Prevention Paradigm

Current cholesterol-focused strategies have achieved historically unprecedented reductions in acute cardiovascular mortality, yet substantial gaps remain. The longstanding focus on 10-year risk estimation in middle-aged individuals frequently misidentifies those with high lifetime risk who could benefit from earlier intervention.¹

Persistent Gaps in Current Models

Metabolic oversight remains a critical vulnerability: traditional LDL-C metrics systematically underestimate cardiovascular risk in individuals with insulin resistance or type 2 diabetes, who may have elevated atherogenic particle burdens (as reflected by ApoB) despite apparently ‘normal’ LDL-C.¹³ Genetic blind spots persist, as standard lipid panels have historically been unable to detect elevated Lp(a) or polygenic predispositions to high LDL-C.²² Furthermore, the shift from AMI mortality toward heart failure, hypertensive heart disease, and arrhythmias—documented in the 2025 JAHA analysis—indicates that contemporary medicine is managing the sequelae of atherosclerosis rather than eradicating the disease process early enough in the life course.²⁶

The 2026 Framework: Precision, Biomarker Refinement, and Genomic Integration

The 2026 ACC/AHA Dyslipidemia Guideline represents a move toward ‘precision prevention.’ Key advances include earlier risk assessment (beginning at age 30), use of the PREVENT equations for both 10- and 30-year risk estimates, selective incorporation of ApoB to resolve LDL-C/particle discordance, and universal one-time Lp(a) testing.¹ The guideline also endorses selective use of 冠動脈石灰化スコア（CACスコア） for risk 再分類 in individuals with borderline or intermediate 10-year risk.¹

Table 7. Key Advances in the 2026 Precision Prevention Framework

Advancement	Description	Impact on Risk Assessment
PREVENT Equations	10- and 30-year risk tools incorporating kidney function (eGFR) and 代謝の健康; replaces Pooled Cohort Equations, which overestimated 10-year risk by 40–50%.	Enables quantification of lifetime risk in younger adults (ages 30–79), facilitating early lifestyle and pharmacological intervention.
Selective ApoB Measurement	Quantifies total atherogenic particle burden; resolves LDL-C/ApoB discordance.	Identifies metabolically unhealthy individuals whose risk is systematically underestimated by LDL-C.
Universal Lp(a) Screening	One-time measurement recommended for all adults to detect inherited Lp(a) elevation.	Identifies the ~20–25% of the population with genetically elevated Lp(a) who carry 残留リスク not addressed by conventional therapy.
CAC Scoring	Selective use for risk reclassification in borderline- and intermediate-risk individuals.	Provides direct anatomic evidence of 無症候性動脈硬化症 to guide statin initiation or de-intensification decisions.
Polygenic Risk Scores (PRS)	Combines thousands of common genetic variants into a composite cardiovascular disease risk score.	Reclassifies individuals with ‘borderline’ clinical risk to high-risk based on genetic susceptibility; incorporated into 2026 guideline narrative.

Sources: Blumenthal et al. (2026); Khan et al. (2024); Khera et al. (2018).

In conclusion, the evolution of cardiovascular care since the 1960s has been a journey from managing crises to modifying biology. While the ‘average’ Western population remains at a pathologically elevated baseline, the tools available in 2026 allow for a level of personalized, life-course prevention that could theoretically render atherosclerotic events increasingly rare rather than the leading cause of death. Future research must prioritize cost-effectiveness and equitable scalability of advanced biomarker testing, as well as the long-term impact of ‘primordial’ prevention strategies aimed at maintaining LDL-C and ApoB at near-physiological levels throughout adult life.¹¹⁰¹⁴

参考文献

1. Writing Committee Members, Blumenthal RS, Morris PB, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Published online March 13, 2026. doi:10.1161/CIR.0000000000001423
2. Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I. J Lipid Res. 2004;45(9):1583-1593. doi:10.1194/jlr.R400003-JLR200
3. Carroll MD, Lacher DA, Sorlie PD, et al. Trends in serum lipids and lipoproteins of adults, 1960-2002. JAMA. 2005;294(14):1773-1781. doi:10.1001/jama.294.14.1773
4. Hooper L, Martin N, Jimoh OF, Kirk C, Foster E, Abdelhamid AS. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2020;5(5):CD011737. Published 2020 May 19. doi:10.1002/14651858.CD011737.pub2
5. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel. Arch Intern Med. 1988;148(1):36-69.
6. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351-364. doi:10.1001/jama.1984.03340270029025
7. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-1278. doi:10.1016/S0140-6736(05)67394-1
8. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934. doi:10.1016/j.jacc.2013.11.002
9. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
10. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144
11. Reiner Ž. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiol. 2017;14(7):401-411. doi:10.1038/nrcardio.2017.31
12. Carroll MD, Fryar CD, Gwira JA, Iniguez M. Total and High-density Lipoprotein Cholesterol in Adults: United States, August 2021-August 2023. NCHS Data Brief. 2024;(515):CS354900. doi:10.15620/cdc/165796
13. Tsoupras A, Lordan R, Zabetakis I. Inflammation, not Cholesterol, Is a Cause of Chronic Disease. Nutrients. 2018;10(5):604. Published 2018 May 12. doi:10.3390/nu10050604
14. Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet. 1999;354(9186):1234-1241. doi:10.1016/S0140-6736(99)02131-5
15. Kaplan H, Thompson RC, Trumble BC, et al. Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. Lancet. 2017;389(10080):1730-1739. doi:10.1016/S0140-6736(17)30752-3
16. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141-1156. doi:10.1016/j.jacc.2018.06.046
17. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995;15(5):551-561. doi:10.1161/01.atv.15.5.551
18. Ivanova EA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN. Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. Oxid Med Cell Longev. 2017;2017:1273042. doi:10.1155/2017/1273042
19. Witt C, Renfroe LG, Lyons TS. Discordance between serum cholesterol concentration and atherogenic lipoprotein particle number in people with metabolic disease: A systematic review. Diabetes Obes Metab. 2025;27(6):2940-2954. doi:10.1111/dom.16335
20. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation. 2005;112(22):3375-3383. doi:10.1161/CIRCULATIONAHA.104.532499
21. Ivanova EA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN. Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. Oxid Med Cell Longev. 2017;2017:1273042. doi:10.1155/2017/1273042
22. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69(6):692-711. doi:10.1016/j.jacc.2016.11.042
23. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43(39):3925-3946. doi:10.1093/eurheartj/ehac361
24. Coassin S, Kronenberg F. Lipoprotein(a) beyond the kringle IV repeat polymorphism: The complexity of genetic variation in the LPA gene. Atherosclerosis. 2022;349:17-35. doi:10.1016/j.atherosclerosis.2022.04.003
25. Perez AD, Simpson RJ Jr, Komé AM, Lopez ST. Emerging therapies targeting lipoprotein(a): Pharmacologic advances and future directions. J Pharmacol Exp Ther. 2025;392(12):103695. doi:10.1016/j.jpet.2025.103695
26. King SJ, Wangdak Yuthok TY, Bacong AM, et al. Heart Disease Mortality in the United States, 1970 to 2022. J Am Heart Assoc. 2025;14(13):e038644. doi:10.1161/JAHA.124.038644
27. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356(23):2388-2398. doi:10.1056/NEJMsa053935
28. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681. doi:10.1016/S0140-6736(10)61350-5
29. Byrne P, Demasi M, Jones M, Smith SM, O’Brien KK, DuBroff R. Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment: A Systematic Review and Meta-analysis. JAMA Intern Med. 2022;182(5):474-481. doi:10.1001/jamainternmed.2022.0134